Leptin induces tube formation in first-trimester extravillous trophoblast cells.

OBJECTIVES: To study the roles of leptin on tube formation (as a measure of cellular angiogenesis) and expression of associated genes in first-trimester human extravillous trophoblast cells.

STUDY DESIGN: The effects of leptin on tube formation and fatty acid uptake in first trimester extravillous placental trophoblast cells, HTR8/SVneo, were investigated. We also investigated the effects of leptin on the expression of genes involved in angiogenesis and lipid metabolism in these cells.

RESULTS: Leptin at 25 ng/ml maximally stimulated tube formation in the first trimester placental trophoblast cells, HTR8/SVneo, by increasing tube length as well as numbers (10,100 ± 150 pixels) compared with those of control cells (2900 ± 50 pixels) p>0.05. Leptin-induced tube formation was not inhibited by the selective inhibitor of VEGF, indicating that its action was independent of VEGF. Leptin, however, significantly increased the expression of genes those are involved in angiogenesis pathways such as PECAM1, JAG1, CDH5, IL8, NRP1, SPHK1, S1PR1, CXCL 1 and 6, FGF1, EFNA3 and AKT1, as determined by PCR array. Leptin did not, however, stimulate expression of the primary angiogenic factors known in placenta such as VEGF or ANGPTL4, as determined by both qRTPCR and PCR array assays. Leptin increased 7-fold expression of FABP4, which is known to be involved in VEGF-mediated angiogenesis in endothelial cells. In addition, leptin treatment resulted a 48% increase in the uptake of docosahexaenoic acid, 22:6n-3 (DHA) which also stimulates tube formation in these cells.

CONCLUSIONS: Leptin may play an important role in early placentation by stimulating several genes involved in angiogenic signalling pathway and fatty acid metabolism.